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CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-β signaling

Oncogene (2018) | Download Citation

Abstract

Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co-repressor abundantly expressed in many types of cancer and regulates genes involved in cancer initiation, progression, and metastasis. We found that CtBP regulates intracellular cholesterol homeostasis in breast cancer cells by forming a complex with ZEB1 and transcriptionally repressing SREBF2 expression. Importantly, CtBP repression of intracellular cholesterol abundance leads to increased EMT and cell migration. The reason is that cholesterol negatively regulates the stability of TGF-β receptors on the cell membrane. Interestingly, TGF-β is also capable of reducing intracellular cholesterol relying on the increased recruitment of ZEB1 and CtBP complex to SREBF2 promoter. Thus, we propose a feedback loop formed by CtBP, cholesterol, and TGF-β signaling pathway, through which TGF-β triggers the cascade that mobilizes the cancer cells for metastasis. Consistently, the intravenous injection of breast cancer cells with ectopically CtBP expression show increased lung metastasis depending on the reduction of intracellular cholesterol. Finally, we analyzed the public breast cancer datasets and found that CtBP expression negatively correlates with SREBF2 and HMGCR expressions. High expression of CtBP and low expression of SREBF2 and HMGCR significantly correlates with high EMT of the primary tumors.

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Acknowledgements

The authors thank the animal facility, Single Cell & Gene expression Analysis Core of Faculty of Health Science for their support of this work.

Author contribution

ZZ, JL, YM, PL, and CZ performed the experiments and analyzed data; DH, LW, and YW analyzed data; HZ and KG discussed the manuscript; LW and DL, wrote the manuscript and supervised the research.

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    • Dapeng Hao

    Present address: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

Affiliations

  1. Cancer Center, Faculty of Health Sciences, University of Macau, Macau, China

    • Zhiqiang Zhao
    • , Dapeng Hao
    • , Li Wang
    • , Jingjing Li
    • , Yuan Meng
    • , Peipei Li
    • , Yuan Wang
    • , Chao Zhang
    •  & Li-jun Di
  2. Metabolomics Core, Faculty of Health Sciences, University of Macau, Macau, China

    • Li Wang
  3. Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China

    • Haisheng Zhou
  4. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA

    • Kevin Gardner

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Funding

DL is supported by the Science and Technology Development Fund (FDCT) of Macao SAR (FDCT 014/2018/A1), the Multi-Year Research Grant from the University of Macau (MYRG2018–00158-FHS), and National Natural Science Foundation of China (grant no. 81772980). LW is supported by the Multi-Year Research Grant from the University of Macau (MYRG2016–00251-FHS). HZ is supported by National Natural Science Foundation of China (grant no. 81372911, 81772909). DH is supported by National Natural Science Foundation of China (grant no. 31701153).

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The authors declare that they have no conflict of interest.

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Correspondence to Li-jun Di.

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https://doi.org/10.1038/s41388-018-0570-z